Congenital Myasthenic Syndrome 16
In a 26-year-old Lebanese woman, born of consanguineous parents, with congenital myasthenic syndrome-16 (CMS16; 614198), Habbout et al. (2016) identified a homozygous c.4360C-T transition (c.4360C-T, NM_000334.4) in exon 24 of the SCN4A gene, resulting in an arg1454-to-trp (R1454W) substitution in the DIVS4 domain. Each unaffected parent was heterozygous for the mutation. In vitro functional expression studies showed that the mutation resulted in a loss-of-function effect, with slowed current decay, slowed fast inactivation, and increased activation time compared to wildtype. Slowed inactivation was also disturbed. Current density was not affected, but there was a decrease in current amplitude in response to repetitive stimulation above 10 Hz. The findings thus showed a combination of gating behaviors that favor the inactivation state; defective inactivation may induce fatigable weakness during muscle firing. The phenotype in this patient comprised both CMS and normokalemic periodic paralysis.
Classic Congenital Myopathy 22A
For discussion of the c.4360C-T transition in the SCN4A gene, resulting in an R1454W mutation, that was found in compound heterozygous state in a patient with classic congenital myopathy-22A (CMYO22A; 620351) by Berghold et al. (2022), see 603967.0042. Berghold et al. (2022) noted that the R1454W variant was present at a low frequency (1.6 x 10(-5)) in heterozygous state in the gnomAD database.
